EP1931677A2 - Nouveaux pyrazolopyrimidines en tant qu'inhibiteurs des kinases dependantes des cyclines - Google Patents

Nouveaux pyrazolopyrimidines en tant qu'inhibiteurs des kinases dependantes des cyclines

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Publication number
EP1931677A2
EP1931677A2 EP20060836186 EP06836186A EP1931677A2 EP 1931677 A2 EP1931677 A2 EP 1931677A2 EP 20060836186 EP20060836186 EP 20060836186 EP 06836186 A EP06836186 A EP 06836186A EP 1931677 A2 EP1931677 A2 EP 1931677A2
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compound
mmol
cdci
prepared
mixture
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EP1931677B1 (fr
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Timothy J. Guzi
Kamil Paruch
Michael P. Dwyer
Marc Labroli
Kartik M. Keertikar
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Merck Sharp and Dohme LLC
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Schering Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present invention relates to pyrazolo[1 ,5-a]pyrimidine compounds useful as protein kinase inhibitors (such as for example, the inhibitors of the cyclin-dependent kinases, mitogen-activated protein kinase (MAPK/ERK), glycogen synthase kinase 3(GSK3beta) and the like), pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases such as, for example, cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, and fungal diseases.
  • diseases such as, for example, cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, and fungal diseases.
  • Protein kinase inhibitors include kinases such as, for example, the inhibitors of the cyclin-dependent kinases (CDKs), mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), and the like. Protein kinase inhibitors are described, for example, by M. Hale et al in WO02/22610 A1 and by Y. Mettey et al in J. Med. Chem., (2003) 46 222-236. The cyclin-dependent kinases are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation.
  • CDKs cyclin-dependent kinases
  • MAPK/ERK mitogen activated protein kinase
  • GSK3beta glycogen synthase kinase 3
  • Protein kinase inhibitors are described, for example, by M. Hale et al in
  • CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, CDK9 and the like perform distinct roles in cell cycle progression and can be classified as either G1 , S, or G2M phase enzymes.
  • Uncontrolled proliferation is a hallmark of cancer cells, and misregulation of CDK function occurs with high frequency in many important solid tumors.
  • CDK2 and CDK4 are of particular interest because their activities are frequently misregulated in a wide variety of human cancers.
  • CDK2 activity is required for progression through G1 to the S phase of the cell cycle, and CDK2 is one of the key components of the G1 checkpoint.
  • Checkpoints serve to maintain the proper sequence of cell cycle events and allow the cell to respond to insults or to proliferative signals, while the loss of proper checkpoint control in cancer cells contributes to tumorgenesis.
  • the CDK2 pathway influences tumorgenesis at the level of tumor suppressor function (e.g. p52, RB, and p27) and oncogene activation (cyclin E).
  • tumor suppressor function e.g. p52, RB, and p27
  • cyclin E oncogene activation
  • Both the coactivator, cyclin E, and the inhibitor, p27, of CDK2 are either over - or underexpressed, respectively, in breast, colon, nonsmall cell lung, gastric, prostate, bladder, non-Hodgkin's lymphoma, ovarian, and other cancers. Their altered expression has been shown to correlate with increased CDK2 activity levels and poor overall survival.
  • CDK inhibitors are known.
  • flavopiridol (Formula I) is a nonselective CDK inhibitor that is currently undergoing human clinical trials, A. M. Sanderowicz et al, J. Clin. Oncol. (1998) 16, 2986-2999.
  • CDK inhibitors include, for example, olomoucine (J. Vesely et al, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I. Meijer et al, Eur. J. Biochem., (1997) 243, 527-536).
  • U.S. 6,107,305 describes certain pyrazolo[3,4-b] pyridine compounds as CDK inhibitors.
  • An illustrative compound from the '305 patent has the Formula II:
  • the present invention provides a novel class of pyrazolo[1 ,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.
  • the present application discloses a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in Formula III:
  • R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), -(CHR 5 ) n -aryl, -(CHR 5 ) n -
  • heteroaryl wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, -OR 5 , -NR 5 R 10 , -C(R 4 R 5 ) P -R 9 , -N(R 5 )Boc, -(CR 4 R 5 ) P OR 5 , -C(O 2 )R 5 , -C(O)R 5 , -C(O)NR 5 R 10 , -SO 3 H, -SR 10 , -S(O 2 )R 7 , -S(O 2 )NR 5 R 10 , -
  • R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or
  • R 2 wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, -CN, -OR 5 , -SR 5 , -S(O 2 )R 6 , -S(O 2 )NR 5 R 6 , -NR 5 R 6 , -C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
  • R 3 is selected from the group consisting of H, halogen, -NR 5 R 6 , -OR 6 , -SR 6 , -C(O)N(R 5 R 6 ), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl
  • each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, -OCF 3 , -(CR 4 R 5 ) P OR 5 , -OR 5 , -NR 5 R 6 , -(CR 4 R 5 ) P NR 5 R 6 , -C(O 2 )R 5 , -C(O)R 5 , -C(O)NR 5 R 6 , -SR 6 , -S(O 2 )R 6 , -S(O 2 )NR 5 R
  • R 5 is H, alkyl, aryl, heteroaryl or cycloalkyl
  • R 6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, -OR 5 , -NR 5 R 10 , -C(R 4 R 5 VR 9 , -N(R 5 )Boc, -(CR 4 R 5 ) P OR
  • R 9 is selected from the group consisting of halogen, -CN, -NR 5 R 10 , -SCN, -NO 2 , -C(O)R 5 , -C(O 2 )R 6 , -C(O)NR 5 R 10 , -OR 6 , -SR 6 , -S(O 2 )R 7 , -S(O 2 )NR 5 R 10 , -N(R 5 )S(O 2 )R 7 , -N(R 5 )C(O)R 7 and -N(R 5 )C(O)NR 5 R 10 ; m is O to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R 2 is phenyl, R 3 is not alkyl, alkynyl or halogen, and
  • any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms.
  • the compounds of Formula III can be useful as protein kinase inhibitors and can be useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of neurodegenerative diseases such Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.
  • the present invention discloses pyrazolo[1 ,5- ajpyrimidine compounds which are represented by structural Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as described above.
  • R is -(CHR 5 ) n -aryl, -(CHR 5 ) n -heteroaryl, -(CHR 5 )n-heteroaryl (with said heteroaryl being substituted with an additional, same or different, heteroaryl), -(CHR 5 ) n -heterocyclyl (with said heterocyclyl being substituted with an additional, same or different, heterocyclyl), or
  • R 2 is halogen, CF 3 , CN, lower alkyl, alkyl substituted with -OR 6 , alkynyl, aryl, heteroaryl or heterocyclyl.
  • R 3 is H, lower alkyl, aryl, heteroaryl, cycloaikyl, -NR 5 R 6 ,
  • R 4 is H or lower alkyl.
  • R 5 is H, lower alkyl or cycloalkyl.
  • n 1 to 2.
  • R is -(CHR 5 ) n -aryl, -(CHR 5 ) n -heteroaryl.
  • R 2 is halogen, CF 3 , CN, lower alkyl, alkynyl, or alkyl substituted with -OR 6 .
  • R 2 is lower alkyl, alkynyl or Br.
  • R 3 is H, lower alkyl, aryl,
  • alkyl, aryl and the heterocyclyl moieties shown immediately above for R 3 are optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CF 3 , lower alkyl, hydroxyalkyl, alkoxy, -S(O 2 )R 5 , and CN.
  • R 4 is H.
  • R 5 is H, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 8 is alkyl or hydroxyalkyl. In an additional embodiment, n is 1. In an additional embodiment, p is 1 or 2. In another embodiment, R is H. In another embodiment, R 2 is halogen.
  • R 2 is thiophene, furan, pyridine, pyrazole, alkylthio or arylthio, wherein each of said alkyl and aryl of R 2 can independently be unsubstituted or substituted as defined above.
  • R 2 is thiophene, furan, pyridine or pyrazole. In another embodiment, R 2 is an amide which can be unsubstituted or substituted as defined above.
  • R 2 is an urea, which may be unsubstituted or substituted as defined above.
  • R 2 is an alkehyl. In another embodiment, R 2 is an alkynyl.
  • R3 is -NR 5 R 6 .
  • R 4 is H.
  • R 4 is unsubstituted lower alkyl.
  • R 4 is alkyl substituted with -OR 6 .
  • R 4 is halo.
  • R 4 is -F, -Cl or -Br. In another embodiment, both R 2 and R 4 are halogen. In another embodiment, both R 2 and R 4 are halo and R is H. In another embodiment, R is H, R 2 is halo and R 3 is heteroaryl. In another embodiment, R is H, R 2 is halo and R 3 is aryl.
  • R is H
  • R 2 is halo
  • R 3 is heterocyclyl.
  • Another embodiment discloses the inventive compounds shown in Table 1, which exhibited CDK2 inhibitory activity of about 0.0001 ⁇ M to > about 5 ⁇ M. The assay methods are described later (from page 333 onwards).
  • Another embodiment of the invention discloses the following compounds, which exhibited CDK2 inhibitory activity of about 0.0001 ⁇ M to about O. ⁇ M:
  • Another embodiment of the invention discloses the following compounds, which exhibited CDK2 inhibitory activity of about 0.0001 ⁇ M to about 0.1 ⁇ M:
  • Patient includes both human and animals.
  • “Mammal” means humans and other mammalian animals.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain.
  • Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain.
  • More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
  • Lower alkyl means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • Alkyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) 2 , carboxy and -C(O)O-alkyl.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • Alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl).
  • substituents include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • alkylene include methylene, ethylene and propylene.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • Alkynyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
  • heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2- a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyri
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • “Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non- limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
  • Cycloalkylalkyl means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like.
  • Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
  • Cycloalkenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • Heteroarylalkyl means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • Heterocyclyl may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
  • Heterocyclylalkyl means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
  • Heterocyclenyl means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, 1 ,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4- dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like.
  • Heterocyclenyl may also mean a single moiety (e.
  • Heterocyclenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • hetero-atom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • N, O or S there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl.
  • suitable alkynylalkyl groups include propargylmethyl.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described.
  • the bond to the parent moiety is through the carbonyl.
  • Preferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described.
  • the bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aralkyloxy means an aralkyl-O- group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
  • Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • Non-limiting example of a suitable aralkylthio group is benzylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-C(O)- group.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O2)- group. The bond to the parent moiety is through the sulfonyl.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • purified refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
  • purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene etal, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) .14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • prodrug means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (III) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci- Ca)alkyl, (C 2 -Ci 2 )alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl-1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 - (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl-1 - (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrCe)alkanoyloxymethyl, 1- ((CrC 6 )alkanoyloxy)ethyl, 1 -methyl-1 -((C r C 6 )alkanoyloxy)ethyl, (C 1 - C-6)alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonylaminomethyl, succinoyl, ⁇ -amino(Ci-C 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ - aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(C 1 - Ce)al
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (Ci-Cio)alkyl, (C 3 -C7) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (C r C ⁇ )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (C 1 -G 4 ) alkyl and Y 3 is (Ci-C 6 )alkyl, carboxy (CrC 6 )alkyl, amino(Ci-C 4 )alkyl or mono-N— or di-N
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical ScL, 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the compounds of Formula III can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula III herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the Formula III may be formed, for example, by reacting a compound of Formula III with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci_ 4 alkyl, or Ci -4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or a
  • the phosphate esters may be further esterified by, for example, a Ci -2 o alcohol or reactive derivative thereof, or by a 2,3-di (C 6-24 )acyl glycerol.
  • Compounds of Formula III, and salts, solvates, esters and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
  • the compounds of Formula (III) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (III) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers.
  • a compound of Formula (III) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • the compounds of Formula (III) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (III) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • salt is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Certain isotopically-labelled compounds of Formula (III) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labelled compounds of Formula (III) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients.
  • the bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents”.
  • the bulk composition is material that has not yet been formed into individual dosage units.
  • An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
  • the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
  • the compounds according to the invention have pharmacological properties; in particular, the compounds of Formula III can be inhibitors of protein kinases such as, for example, the inhibitors of the cyclin-dependent kinases, mitogen-activated protein kinase (MAPK/ERK), glycogen synthase kinase 3(GSK3beta) and the like.
  • the cyclin dependent kinases (CDKs) include, for example, CDC2 (CDK1), CDK2, CDK4, CDK5, CDK6, CDK7 CDK8 and CDK9.
  • novel compounds of Formula III are expected to be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease.
  • proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease.
  • proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease.
  • the compounds of Formula III can be useful in the treatment of a variety of cancers, including (but not limited to) the following: carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodys
  • inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
  • any disease process e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
  • Compounds of Formula III may also be useful in the treatment of Alzheimer's disease, as suggested by the recent finding that CDK5 is involved in the phosphorylation of tau protein (J. Biochem, (1995) 117, 741-749). Compounds of Formula III may induce or inhibit apoptosis. The apoptotic response is aberrant in a variety of human diseases.
  • Compounds of Formula III as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections (including but not limited to herpevirus, poxvirus, Epstein- Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia,
  • Compounds of Formula III can modulate the level of cellular RNA and DNA synthesis. These agents would therefore be useful in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).
  • viral infections including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus.
  • Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse.
  • Compounds of Formula III may also be useful in inhibiting tumor angiogenesis and metastasis.
  • Compounds of Formula III may also act as inhibitors of other protein kinases, e.g., protein kinase C, her2, raf 1 , MEK1 , MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, AbI and thus be effective in the treatment of diseases associated with other protein kinases.
  • Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition associated with the CDKs by administering a therapeutically effective amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound to the mammal.
  • a preferred dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula III.
  • An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound.
  • the compounds of this invention may also be useful in combination
  • anti-cancer treatments such as radiation therapy
  • anti-cancer agents selected from the group consisting of cytostatic agents, cytotoxic agents (such as for example, but not limited to, DNA interactive agents (such as cisplatin or doxorubicin)); taxanes (e.g.
  • topoisomerase Il inhibitors such as etoposide
  • topoisomerase I inhibitors such as irinotecan (or CPT-11 ), camptostar, or topotecan
  • tubulin interacting agents such as paclitaxel, docetaxel or the epothilones
  • hormonal agents such as tamoxifen
  • thymidilate synthase inhibitors such as 5-fluorouracil
  • anti-metabolites such as methoxtrexate
  • alkylating agents such as temozolomide (TEMODARTM from Schering-Plough Corporation, Kenilworth, New Jersey), cyclophosphamide); Famesyl protein transferase inhibitors (such as, SARASARTM(4-[2-[4-[(11 R)- 3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1 ,2-b
  • anti-cancer also known as anti-neoplastic
  • anti-neoplastic agents include but are not limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,
  • Triethylenethiophosphoramine Busulfan, Carmustine, Lomustine, Streptozocin, dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATINTM from Sanofi-Synthelabo Pharmaeuticals, France), Pentostatine, Vinblastine,
  • Hexamethylmelamine Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225 (or Cetuximab from Merck KGaA, Darmstadt, Germany), and Campath.
  • the compounds of this invention may specifically be useful in combination (administered together, concurrently or sequentially) with temozolomide and/or radiation therapy.
  • such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.
  • the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell ScL, (1995) 108, 2897.
  • Compounds of Formula III may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; compounds of Formula III may be administered either prior to or after administration of the known anticancer or cytotoxic agent.
  • cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians.
  • this invention includes combinations comprising an amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, and an amount of one or more anti-cancer treatments and anti-cancer agents listed above wherein the amounts of the compounds/ treatments result in desired therapeutic effect.
  • compositions which comprise at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compounds of this invention may also be delivered subcutaneously.
  • the compound is administered orally or intravenously.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • kits comprising an amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound and an amount of at least one anticancer therapy and/or anti-cancer agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
  • Varian VXR-200 (200 MHz, 1 H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically.
  • analyses was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33mm x 7mm ID; gradient flow: 0 min - 10% CH 3 CN, 5 min - 95% CH 3 CN, 7 min - 95% CH 3 CN, 7.5 min - 10% CH 3 CN, 9 min - stop.
  • the retention time and observed parent ion are given.
  • the following solvents and reagents may be referred to by their abbreviations in parenthesis:
  • the chlorides of type 9 can be prepared by treatment of the pyridones 8 with POCI 3 .
  • R 2 is equal to H, substitution in this position is possible on the compounds of type 9 by electrophilic halogenation, acylation, and various other electrophilic aromatic substitutions.
  • the chlorides of type 14 can be prepared by treatment of the pyridones 13 with POCI 3 .
  • R 2 is H, substitution in this position is possible on compounds of type 9 by electrophilic halogenation, acylation, and various other electrophilic aromatic substitutions.
  • N7-amino functionality can be accomplished through regioselective displacement of the chloride of compounds of type 14. Incorporation of the N5-amino functionality by addition of an appropriate amine at higher temperature.
  • the chlorides of type 14 can be prepared by treatment of the pyridones
  • the resulting slurry was filtered through a plug of Celite.
  • the Celite was washed with CH 3 OH and the filtrate dried with Na 2 SO 4 , filtered, and concentrated.
  • the product was purified by flash chromatography using a CH 2 CI 2 : CH 3 OH (93 : 7) solution as eluent to yield aldehyde as the first eluting product and alcohol as the second eluting product.
  • STEP A A solution of aldehyde (50 g, 0.41 mol) [WO 0232893] in MeOH (300 ml_) was cooled to 0 0 C and carefully treated with NaBH 4 (2Og, 0.53 mol in 6 batches) over 20 minutes. The reaction was then allowed to warm to 20 0 C and was stirred for 4 hours. The mixture was again cooled to 0 0 C, carefully quenched with saturated aqueous NH 4 CI, and concentrated. Flash chromatography (5- 10% 7N NH 3 -MeOH/CH 2 CI 2 ) provided the primary alcohol (31 g, 62%) as a light yellow solid.
  • STEP B A solution of aldehyde (50 g, 0.41 mol) [WO 0232893] in MeOH (300 ml_) was cooled to 0 0 C and carefully treated with NaBH 4 (2Og, 0.53 mol in 6 batches) over 20 minutes. The reaction was then allowed to warm to 20 0 C and was stirred for 4
  • Pd(PPh 3 )4 0.404 gm, 0.35 mmol was added to a degassed solution of 4-cyanobenzene boronic acid ( 1.029 g, 7 mmol ) and 2-bromopyridine ( 1.11 g, 7 mmol ) in 75 mL acetonitrile.
  • 0.4 M sodium carbonate solution 35 ml_ was added to the reaction mixture and the resulting solution was refluxed at 9O 0 C under Ar for 24 hours ( progress of reaction was monitored by TLC ).
  • the reaction mixture was cooled and aqueous layer was separated.
  • the organic layer containing the product and spent catalyst was mixed with silica gel ( 15 g ) and concentrated to dryness.
  • 3(R/S)-(tert-Butoxycarbonylaminomethyl)piperidine (3g, 14.0mmoles) was dissolved in anhydrous dichloromethane (5OmL) and trimethylsilylisocyanate (9.68g, 11.4mL, 84.0mmoles) was added. The mixture was stirred under argon at 25°C for 68h. Additional trimethylsilylisocyanate (4.84g, 5.7mL, 42.0mmoles) was added and the mixture was stirred at 25°C for a total of 9Oh.
  • 3-(2-tert-Butoxycarbonylaminoethyl)piperidine (500mg, 2.19mmoles) was dissolved in anhydrous dichloromethane (1OmL) and trimethylsilylisocyanate (2.96ml_, 21.9mmoles) was added. The mixture was stirred under argon at 25°C for 3.35h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate.
  • 3-(2-tertutoxycarbonylaminoethyl)piperidine-1-carboxamide (392.7mg, 1.45mmoles) (prepared as described in Preparative Example 242, Step A above) was dissolved in methanol (7.5mL) and 10% cone, sulfuric acid in 1 ,4-dioxane (19.5mL) was added. The mixture was stirred at 25 0 C for 1.25h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH " form) was added until the pH was basic.
  • 1-Methylisonipecotamide (6.75g, 47.5mmoles) (prepared as described in Preparative Example 245, Step A above) was dissolved in anhydrous THF (35OmL) and the resulting mixture was added in portions to a stirred slurry of lithium aluminum hydride (1.8g, 47.5mmoles) in anhydrous THF (10OmL) at 0 0 C under nitrogen. The mixture was stirred at 0 0 C for 30min and then heated at 66°C for 25h under nitrogen.
  • Example 28 1 H NMR (CDCI 3 ) ⁇ 8.86 (s, 1H), 8.74 (m, 1H), 8.17 (s, 1H), 7.97
  • Example 110 1 H NMR (CDCI 3 ) ⁇ 8.18(t, 1H) 1 8.03(s, 1H) 1 7.44(m, 1H), 7.30(t,
  • Example 112 1 H NMR (CDCI 3 ) ⁇ 8.22(t, 1 H), 8.15(s, 1 H) 1 7.51-7.33(m, 7H) 1
  • Example 116 1 H NMR (CDCI 3 ) ⁇ 8.67(s, 1H), 8.55(d, 1H), 8.50(s, 1H), 7.92(d, 1 H), 7.90(d, 1 H), 7.78(t, 1 H), 7.10(d, 1 H), 6.97(s, 1H), 5.11(s, 2H), 3.77(s, 6H)
  • Example 117 1 H NMR (CDCI 3 ) ⁇ 8.38(s, 1 H), 8.30(d, 1 H) 1 8.17(s, 1 H), 7.52- 7.37(m, 6H), 6.97(t, 1H), 6.13(s, 1H), 4.77(d, 2H), 2.50(s, 3H)
  • Example 118 1 H NMR (CDCI 3 ) ⁇ 8.18(t, 1H), 8.03(s, 1H), 7.44(m, 1H), 7.30(t, 1 H), 7.17(q, 1 H), 6.66(s, 1 H), 6.56(br, 1 H),
  • Example 126 _ 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.5 (d, 1 H), 7.42 - 7.35 ( m, 2H), 7.3 -7.2 (m, 2H), 7.15 (dd, 1H), 7.1 (dd, 1H), 7.0 (t, 1H), 6.6 (s, 1H), 4.8 ( d, 2H).
  • Example 127 1 H NMR (CDCI 3 ) ⁇ 8.2 (dt, 1 H), 8.0 (s,1 H), 7.4 (dd, 1 H), 7.3- 7.25 (m, 3H), 7.1 (dd, 1 H), 6.9 - 6.85 (m, 2H), 6.7 (t, 1 H), 6.6 (s, 1 H), 4.6 (d, 2H), 3.2 (m, 4H), 2.6 (m, 4H), 2.3 (s, 3H)
  • Example 128 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt,1H), 8.1 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.4 (m, 2H), 7.25 (d, 1 H), 7.2 (s,1 H), 7.15 (dd, 1 H), 7.0 (s, 1 H), 6.8 (t, 1 H), 6.6 (s, 1 H), 4.75 (d, 2H).
  • Example 129 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1H), 8.05 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.4 (m, 1 H), 7.3 (dd, 1H), 7.15 (dd, 1H), 6.9 (t, 1 H), 6.5 (s, 1H), 4.75 (d, 2H), 3.85 (s, 3H)
  • Example 130 1 H NMR (CDCI 3 ) ⁇ 8.2 (dt,1 H), 8.0 (s, 1 H), 7.4 (dd, 1 H), 7.3(dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1 H), 6.4 (s,1 H), 4.2 (d, 2H), 3.8 (s, 3H).
  • Example 131 1 H NMR (CDCI 3 ) ⁇ 8.2 (dt, 1 H), 8.0 (s,1 H), 7.4 - 7.15 (m, 3H), 6.7 (t, 1 H), 4.2 (q, 2H), 3.8 (dt, 2H), 2.8 (t, 2H), 1.2 (t, 3H)
  • Example 132 1 H NMR (CDCI 3 ) ⁇ 8.2 (dt, 1H), 8.0 (s,1H), 7.4-7.15 (m, 3H), 6.7 (t, 1H), 4.2 (q, 2H), 3.8 (dt, 2H), 2.8 (t, 2H), 2.05 (m, 2H) 1.2 (t, 3H)
  • Example 134 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1H), 8.0 (s, 1H), 7.95 (d, 2H), 7.6 (d, 2H), 7.4 (m, 1H) 1 7.25 (dd, 1H), 7.1 (dd, 1H) 1 6.9 (t, 1H) 1 6.5 (s, 1H), 4.8 (d, 2H) 1 3.0 (S 1 3H)
  • Example 135 1 H NMR (DMSO d6) ⁇ 9.1 (bs, 2H), 8.4 (s,1H), 8.0 (t, 1H), 7.85 (d, 2H), 7.7 ( ⁇ , 2H) 1 7.6 (m, 1 H) 1 7.4 (m, 2H), 6.6 (s, 1 H) 1 4.8 (bs, 2H)
  • Example 136 1 H NMR (CDCI 3 ) ⁇ 8.2 (dt, 1H) 1 8.0 (s,1H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.9 (m, 3H), 6.7 (t, 1H), 6.5 (s, 1H), 4.5 (d, 2H), 4.2 (s, 4H)
  • Example 137 1 H NMR (CDCI 3 ) ⁇ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.3 (dd, 1H), 7.2 (dd, 1H), 6.9 (dd, 1H) 1 6.8 (t, 1H) 1 6.7 (m, 1H), 6.6 (s, 1H), 5.3 (s, 2H), 4.85 (s, 2H) 1 4.6 (d, 2H).
  • Example 138 1 H NMR (CDCI 3 ) ⁇ 8.2 (dt, 1 H), 8.0 (s, 1 H), 7.9 (d, 1 H), 7.8 (d, 1 H), 7.4 (m, 2H), 7.3 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.6 (s, 1H), 4.8 (d, 2H)
  • Example 139 1 H NMR (CDCI 3 ) ⁇ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.3 (m, 2H), 7.2 (dd, 1H) 1 7.1 (dd, 1H), 6.8 (d, 1H), 6.7 (t, 1H), 6.6(s, 1H), 4.6 (m, 4H) 1 3.2 (t, 2H)
  • Example 140 1 H NMR(CDCI 3 ) ⁇ 8.45 (s, 1H) 1 8.2 (dt, 1H), 8.0 (s, 1H), 7.7 (dd, 1 H), 7.4 - 7.3 (m, 3H), 7.15 (dd, 1 H), 6.8 (t, 1 H) 1 6.6 (s,1 H), 4.7 (d, 2H)
  • Example 141 1 H NMR(CDCI 3 ) ⁇ 8.2 (dt, 1H) 1 8.0 (s, 1H) 1 7.45 - 7.1 (m, 7H) 1 6.6 (s, 1H) 1 4.4 (dt, 2H), 2.6 (t, 2H), 1.8 (m, 2H), 1.4 (m, 2H)
  • Example 173 1 H NMR (DMSO-Of 6 ) ⁇ 8.86 (s, 1H), 8.46 (s, 1 H), 8.32-8.28 (m,
  • Example 181 1 H NMR (300MHz, CDCI 3 ) D 8.41 (s, 1H), 8.28 - 8.23 (d, 1 H),
  • Example 184 1 H NMR (300MHz, CDCI 3 ) D8.96 - 8.90 (s, 1H), 8.08 (s, 1H), 8.04 (d, 1 H), 7.72 (d, 1 H), 7.70 - 7.61 (dd, 1 H), 7.24 - 7.20 (dd, 1 H), 6.92 - 6.84 (t,
  • Example 186 1 H NMR (300MHz, CDCI 3 ) D8.96 - 8.90 (s, 1H), 8.08 (s, 1H), 8.44
  • Example 196 1 H NMR (CD 3 OD) ⁇ 8.73(d, 1H), 8.58(q, 1H), 8.12(s, 1H), 8.00(d,
  • Example 197 1 H NMR (CD 3 OD) ⁇ 8.73(d, 1H), 8.58(q, 1H), 8.12(s, 1H), 8.00(d, 1 H), 7.54(q, 1 H), 6.19(s, 1 H), 4.86(s, 2H), 4.22-4.08(m, 2H), 4.03-3.93(m, 2H), 3.63(m, 1H), 2.50-2.39(m, 1H), 2.32-2.21 (m, 1H).
  • Example 199 1 H NMR (300MHz, CDCI 3 ) D8.29 (s, 1 H), 8.15 (br s, 1H), 7.95 (s, 1 H), 7.28 (d, 1 H), 7.05 - 6.95 (appt t, 1 H), 5.70 (s, 1 H), 4.62 (d, 2H), 2.90 (m, 1 H), 2.30 (m, 1 H), 1.9 - 1.2 (m, 8H), 0.65 (d, 3H).
  • Example 200 1 H NMR (300MHz, CDCI 3 ) D 8.71 (s, 2H), 8.00 (s, 1 H), 6.13 (s, 1 H), 3.59 (s, 2H), 3.01 - 2.58 (m, 1 H), 2.51 - 2.45 (m, 1 H), 2.44 -2.30 (m,1 H), 2.20 (s, 3H), 2.09 - 1.95 (m, 2H), 1.85 -1.70 (m, 2H), 0.80 - 0.76 (d, 3H).
  • Example 203 1 H NMR (300MHz, CDCI 3 ) D8.10 (s, 1 H), 8.08 (s, 1 H), 6.27 (s, 2H), 4.95 (s, 2H), 3.00 - 2.90 (dd, 2H), 2.60 (m, 2H), 2.48 (br s, 1 H), 2.39 (s, 3h), 2.25 m, 1 H), 1.95 - 1.70 (m, 3H).
  • Example 218 By essentially the same procedure set forth in Example 218 combining the compounds shown in Column 1 of Table 20 with the appropriate alcohol , the compounds shown in Column 2 of Table 20 were prepared.
  • Example 227 By essentially the same procedure set forth in Example 227 combining the compounds shown in Column 1 of Table 21 with the appropriate amine, the compounds shown in Column 2 of Table 21 were prepared.
  • Example 236 By essentially the same procedure set forth in Example 236 combining the compounds shown in Column 2 and 3 of Table 22, the compounds shown in Column 4 of Table 22 were prepared.
  • Example 262 By essentially the same procedure set forth in Example 262 starting from the compounds shown in Column 1 of Table 24, the compounds shown in Column 2 of Table 24 were prepared.
  • TFA (0.5 mL) was added to a solution of the compound prepared in Preparative Example 197 (0.08 g, 0.16 mmol) in CH 2 CI 2 (2.0 mL) at O 0 C and the resulting solution stirred 2.5 hours and stored at 4 0 C overnight at which time additional TFA (0.5 mL) was added. The resulting solution was stirred 4 hours and concentrated in vacuo. The residue was neutralized with 1 N NaOH and extracted with CH 2 CI 2 . The combined organics were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step D By essentially the same procedure set forth in Preparative Example 200 only substituting the compound prepared in Example 276, Step B, the above compound was prepared (0.1g, 100% yield). Step D:
  • the palladium-catalyzed zinc cross-coupling reaction was carried out in a manner similar to the procedure described in J. Org. Chem. (1999), 453.
  • a solution of the chloropyrazolopyrimidine (200 mg, 0.458 mmol), Pd(PPh 3 ) 4 (53 mg, 0.046 mmol), and exo-2-norbonylzinc bromide (0.5 M in THF, 0.95 mL, 0.47 mmol) in DMF (2 mL) was refluxed at 100 0 C (oil bath temp.) overnight.
  • the reaction mixture was quenched with half-saturated NH 4 CI and extracted with CH 2 CI 2 .
  • the organic phase was dried over MgSO 4 and concentrated under reduced pressure.
  • Example 304 By essentially the same procedure set forth in Example 304, utilizing the aldehyde from Example 303 and substituting the Grignard or organolithium reagents shown in Column 2 of Table 28, the compounds in Column 3 of Table 28 were prepared:
  • Step B (41 mg, 0.078 mmol) in CH 2 CI 2 (2 mL) was added MCPBA (33 mg, 0.19 mmol) in one portion.
  • the resulting mixture was stirred for 3h at rt and the mixture was diluted with CH 2 CI 2 (5 ml_) and sat. aq. NaHCO 3 (2.5 mL).
  • the layers were separated, the aqueous layer was extracted with CH 2 CI 2 (2 x 5 mL), and the organic layers were combined.
  • the organic layer was dried (Na 2 SO ⁇ , filtered, and concentrated under reduced pressure to afford 40 mg (92%) of the sulfone adduct as a light yellow solid.
  • M+H 560.
  • Step A To a solution of the compound prepared in Example 340, Step A (135 mg, 0.28 mmol) in CH 2 CI 2 (2 ml_) at rt was added TFA (0.54 ml_, 7.0 mmol) dropwise. The resulting solution was stirred for 18 h at rt and was concentrated under reduced pressure. The crude material was redissolved in CH 2 CI 2 (5 mL) and the organic layer was sequentially washed with sat. aq. NaHCO 3 (2 x 2 mL) and brine (1 x 2 mL). The organic layer was dried (Na 2 SO ⁇ , filtered, and concentrated under reduced pressure.
  • Step B Removal to t-butoxycarbonyl protecting group with KOH.
  • Step A To a mixture of the compound prepared in Example 341 , Step A (0.14 g, 0.26 mmol) in EtOH : H 2 O (3 mL, 2 : 1) was added KOH (0.29 g, 20 eq.) in one portion. The resulting solution was stirred at reflux 14 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was taken up in CH 2 CI 2 (5 mL) and diluted with saturated NaHCO3 (2 mL). The layers were separated and the aqueous layer extracted with CH 2 CI 2 (2 x 4 mL). The combined organics were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Example 414 1 H NMR (DMSO-d 6 ) ⁇ 8.26 (s, 1H), 8.23 (m, 1H), 8.13 (m, 1H),
  • N-bromosuccinimide (12 mg, 0.068 mmol) in anhydrous CH 3 CN (2 ml_) was added under N2 to a stirred solution of the compound prepared in Example 428, Step B (18 mg, 0.068 mmol), in anhydrous CH 3 CN (2 ml_). The mixture was stirred at 25 0 C for 2 hr.
  • R 2 H, or Cl
  • EXAMPLE 431 Reactants: 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1 ,5- a]pyrimidine (110mg, 0.318mmoles) (prepared as described in Preparative Example 129); 3-(aminomethyl)piperidine-1-carboxamide (60mg, 0.382mmoles) (prepared as described in Preparative Example 241 above); diisopropyl ethylamine (0.111mL, 0.636mmoles); anhydrous 1 ,4-dioxane (2.5mL).
  • HRFABMS m/z 463.0628 (MH + ). Calcd.
  • EXAMPLE 432 Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1 ,5-a]pyrimidine ( ⁇ OOmg, 1.62mmoles) (prepared as described in Preparative Example 127); 3- (aminomethyi)piperidine-i-carboxamide (306mg, 1.944mmoles) (prepared as described in Preparative Example 241 above); diisopropyl ethylamine (0.566mL, 3.24mmoles); anhydrous 1 ,4-dioxane (13mL). Physical properties: HRFABMS: m/z 429.1031 (MH + ). Calcd.
  • EXAMPLE 433 Reactants: 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1 ,5- ajpyrimidine (347mg, 1.01mmoles) (prepared as described in Preparative
  • Example 129 3-(aminoethyl)piperidine-1-carboxamide (208mg, 1.21mmoles) (prepared as described in Preparative Example 242 above); diisopropyl ethylamine (0.393mL, 2.02mmoles); anhydrous 1 ,4-dioxane (9mL).
  • EXAMPLE 434 Reactants: 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1 ,5- a]pyrimidine (275mg, 0.803mmoles) (prepared as described in Preparative Example 129); 4-(aminoethyl)piperidine-1 ⁇ carboxamide (165mg, 0.963mmoles) (prepared as described in Preparative Example 243 above); diisopropyl ethylamine (0.311mL, 0.963mmoles); anhydrous 1 ,4-dioxane (7.2mL).
  • EXAMPLE 435 Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1 ,5-a]pyrimidine (174mg, 0.507mmoles) (prepared as described in Preparative Example 129) and 3-(aminomethyl)-1-methylpiperidine (65mg, 0.507mmoles) (prepared as described in Preparative Example 244 above); diisopropyl ethylamine (0.178mL, 1.014mmoles); anhydrous 1 ,4-dioxane (2.5ml_).
  • EXAMPLE 436 Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1 ,5-a]pyrimidine (111.4mg, 0.325mmoles) (prepared as described in Preparative Example 129); 4-(aminomethyl)-1-methylpiperidine (50mg, 0.39mmoles) (prepared as described in Preparative Example 245 above); diisopropyl ethylamine (0.1135mL, 0.65mmoles); anhydrous 1 ,4-dioxane (1.5mL).
  • EXAMPLE 437 Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1 ,5-a]pyrimidine (191mg, 0.557mmoles) (prepared as described in Preparative Example 129); 3- (aminomethyl)benzonitrile (88.3mg, 0.668mmoles) (prepared as described in Preparative Example 246 above); diisopropyl ethylamine (0.192mL, 1.114mmoles); anhydrous 1 ,4-dioxane (4.5mL).
  • EXAMPLE 438 Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1 ,5-a]pyrimidine (233.5mg, 0.681 mmoles) (prepared as described in Preparative Example 129); 4-(aminomethyl)benzonitrile (108mg, 0.817mmoles) (prepared as described in Preparative Example 247 above); diisopropyl ethylamine (0.235mL, 1.362mmoles); anhydrous 1 ,4-dioxane (5.3mL).
  • 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1 ,5-a]pyrimidine (50mg, 0.146mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1 ,4-dioxane (5mL) in a GeneVac Technologies carousel reaction tube.
  • PS-diisopropyl ethylamine resin (161mg, 0.5828mmoles) was added to each tube.
  • EXAMPLE 440 Physical properties: HRFABMS: m/z 428.0272 (MH + ). Calcd. for Ci 9 H 16 N 5 BrCI: m/z 428.0278; ⁇ H (CDCI 3 ) 3.28 (2H, dd, C 5 H 4 NCH 2 CH 2 NH-), 3.94 (2H, ddd, C 5 H 4 NCH 2 CH 2 NH-), 6.40 (1 H, s, H 6 ), 7.22-7.29 (3H, m, Ar-H), 7.38- 7.44 (2H, m, Ar-H), 7.51 (1 H 1 m, Ar-H), 7.68 (1 H, ddd, Ar-H), 7.73 (1 H, Ar-H), 8.18 (1 H, s, H 2 ) and 8.68ppm (1 H, NH); ⁇ c (CDCI 3 ) CH 2 : 36.4, 41.5; CH: 87.3, 122.1 , 123.6, 127.1 , 130.1 , 130.1 , 131.6, 137.0,
  • EXAMPLE 442 Physical properties: HRFABMS: m/z 428.0275 (MH + ). Calcd. for C 19 H 16 N 5 BrCI: m/z 428.0278; ⁇ H (CDCI 3 ) 3.13 (2H, dd, CsH 4 NCH 2 CH 2 NH-), 3.80 (2H, ddd, C 5 H 4 NCH 2 CH 2 NH-), 6.42 (1 H, s, H 6 ), 6.53 (1 H, m, Ar-H), 7.23 (2H, m, Ar-H), 7.40-7.46 (2H, m, Ar-H), 7.62 (1 H, m, Ar-H), 7.76 (1 H, m, Ar-H), 8.07 (1H, s, H 2 ) and 8.63ppm (1H, m, NH); ⁇ c (CDCI 3 ) CH 2 : 34.7, 42.5; CH: 87.4, 124.5, 124.5, 127.2, 130.2, 130.3, 131.6, 144.0, 150.2,
  • 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1 ,5-a]pyrimidine (50mg, 0.146mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1 ,4-dioxane (5mL) in a GeneVac Technologies carousel reaction tube.
  • PS-diisopropyl ethylamine resin (161mg, 0.5828mmoles) was added to each tube.
  • EXAMPLE 456 This enantiomer may be prepared by essentially the same manner as described above.
  • 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1 ,5-a]pyrimidine (300mg, 0.875mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1 ,4-dioxane (6.8ml_).
  • 4-( aminomethyl)piperidine-1- carboxylic acid tert-butyl ester (225mg, 1.05mmoles) and diisopropyl ethylamine (0.3055mL, 1.75mmoles) were added and the mixture was heated at 75 0 C for 24h.
  • Example 476-479 A mixture of the compound prepared in Example 129 (300 mg, 0.66 mmol), NaOH (5 g), CH 3 OH -H 2 O (100 mL, 90:10) was stirred at 25 C for about 15 h. Progress of hydrolysis was checked by TLC. Reaction mixture was concentrated to remove methanol. The concentrate was diluted with 50 mL water, and extracted with ether to remove any un-reacted ester. Aqueous solution, thus obtained, was neutralized with 3 N HCI to pH 4 to obtain free acid, filtered and washed repeatedly with water. The acid was dried under vacuum ( 270 mg, 93% ) and used without further purification.
  • Example 476-479 A mixture of the compound prepared in Example 129 (300 mg, 0.66 mmol), NaOH (5 g), CH 3 OH -H 2 O (100 mL, 90:10) was stirred at 25 C for about 15 h. Progress of hydrolysis was checked by TLC. Reaction mixture was concentrated to remove methanol. The concentrate was diluted with 50
  • Example 476 1 H NMR (CDCI 3 ) ⁇ 8.15 (m, 2H), 8.0 (m, 1H), 7.6 (m, 1H), 7.3 (m,
  • Example 477 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd,
  • Example 479 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd,
  • Example 480 By essentially the same procedure set forth in Example 480 only substituting the carboxylic acid shown in Column 2 of Table 40 and the amine shown in Column 3 of Table 40, the compounds shown in Column 4 of Table 40 were prepared.
  • Example 481 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.7 (d, 2H), 7.4 (s,
  • Example 482 1 H NMR (CDCI 3 ) 5 8.15 (dt, 1 H),8.0 (s, 1 H) 1 7.45 - 7.35 (m, 4H),
  • Example 483 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.8 (bs, 1 H), 7.7 (d,
  • Example 484 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.7 (d, 2H), 7.4 (d,
  • Example 486 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H), 7.35 (d, 1H), 7.25 (dd, 1H), 7.1 (dd, 1 H) 1 6.9 (t, 1 H), 6.5 (s, 1H), 6.2 (t, 1 H), 4.7 (d, 2H), 3.3 (dd, 2H) 1 1.05 (m, 1H) 1 0.5 (m, 2H) 1 0.25 (m, 2H).
  • Example 487 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1H), 8.0 (s, 1H) 1 7.7 (d, 2H), 7.4 (d, 2H) 1 7.35 (m, 1H) 1 7.25 (dd, 1H) 1 7.15 (dd, 1H) 1 6.85 (t, 1H), 6.5 (s, 1H), 6.2 (bs, 1 H) 1 4.7 (d, 2H) 1 4.6 (m, 1 H), 2.4 (m, 2H) 1 1.95 (m, 1 H), 1.75 (m, 2H).
  • Example 488 1 H NMR (CDCI 3 ) ⁇ 8.5 (t, 1 H), 8.15 (dt, 1 H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1 H), 7.25 (dd, 1 H), 7.15 (dd, 1 H), 6.8 (t, 1H), 6.5 (s, 1 H), 5.9 (bs, 1 H), 4.7 (d, 2H), 1.4 (s, 9H).
  • Example 489 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1 H), 8.0 (s, 1H) 1 7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1 H), 7.25 (dd, 1 H), 7.15 (dd, 1 H), 6.8 (t, 1 H), 6.5 (s, 1 H), 6.0 bs, 1 H), 4.7 (d, 2H), 4.4 (m, 1 H), 2.05 (m, 2H), 1.7 (m, 4H), 1.4 (m, 2H).
  • Example 490 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1H), 8.0 (s, 1 H), 7.7 (d, 2H) 1 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1 H), 6.5 (s, 1H), 6.5 (bs, 2H), 4.7 (d, 2H), 4.1 (m, 1H), 3.9 - 3.7 (m, 3H), 3.3 (m, 1 H), 2.0 - 1.9 (m, 4H).
  • Example 491 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.45 - 7.35 (m, 5H), 7.25 (dd, 1 H), 7.1 (dd, 1 H), 6.8 (t, 1 H), 6.5 (s, 1 H), 4.7 (d, 2H), 3.7 (bs, 2H),3.3 ( bs, 2H), 1.7 (bs, 4H), 1.5 (bs, 2H).
  • Example 492 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.45 - 7.35 (m, 5H), 7.25 (dd, 1 H), 7.1 (dd, 1 H), 6.85 (t, 1 H), 6.5 (s, 1 H), 4.7 (d, 2H), 3.8 - 3.4 (bm, 8H).
  • Example 493 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1H), 8.0 (s, 1H), 7.45 - 7.35 (m, 5H), 7.25 (dd, 1 H), 7.1 (dd, 1H), 6.80 (t, 1H) 1 6.5 (s, 1H) 1 4.7 (d, 2H) 1 4.0 (m, 2H) 1 3.6 (m, 2H), 2.8 - 2.45 (m, 4H).
  • Example 494 1 H NMR (CH3OD) ⁇ 8.15 (s, 1 H), 8.0 (dt, 1 H) 1 7.45 - 7.35 (m, 5H) 1 7.25 (dd, 1H) 1 7.1 (dd, 1H), 6.80 (t, 1H), 6.5 (s, 1 H), 4.7 (d, 2H), 3.7 (bs, 2H), 3.4 (bs, 2H) 1 2.5 - 2.4 (m, 4H), 2.2 (s, 3H).
  • Example 495 1 H NMR (CDCI 3 ) ⁇ 8.15 (dt, 1H), 8.0 (s, 1 H), 7.45 - 7.35 (m, 5H),

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Abstract

Dans ses différents modes de réalisation, la présente invention a trait à une nouvelle classe de composés pyrazolo[1,5-a]pyrimidine en tant qu'inhibiteurs des kinases dépendantes des cyclines, à des procédés de préparation de tels composés, à des compositions pharmaceutiques contenant un ou plusieurs de ces composés, à la préparation de formulations pharmaceutiques comprenant un ou plusieurs de ces composés, et à des procédés de traitement, de prévention, d'inhibition, ou d'amélioration d'une ou de plusieurs maladies associées aux kinases dépendantes des cyclines mettant en oeuvre ces composés ou compositions pharmaceutiques.
EP06836186.4A 2005-10-06 2006-10-04 Nouveaux pyrazolopyrimidines en tant qu'inhibiteurs des kinases dependantes des cyclines Active EP1931677B1 (fr)

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EP1931677B1 (fr) 2016-04-20
BRPI0616987A2 (pt) 2009-08-04
TW201038271A (en) 2010-11-01
NZ567187A (en) 2011-09-30
ZA200802996B (en) 2009-03-25
IL190510A0 (en) 2008-11-03
US8586576B2 (en) 2013-11-19
JP2012072189A (ja) 2012-04-12
AU2006302443A1 (en) 2007-04-19
RU2008117295A (ru) 2009-11-20
AR056873A1 (es) 2007-10-31
TWI372625B (en) 2012-09-21
PE20070496A1 (es) 2007-07-13
MY162134A (en) 2017-05-31
WO2007044449A2 (fr) 2007-04-19
US20060128725A1 (en) 2006-06-15
US7196078B2 (en) 2007-03-27
WO2007044449A3 (fr) 2007-05-24
ECSP088345A (es) 2008-05-30
TW200800224A (en) 2008-01-01
TWI362263B (en) 2012-04-21
JP2009511487A (ja) 2009-03-19
IL215929A0 (en) 2011-12-29
BRPI0616987B1 (pt) 2021-08-31
CN102627645A (zh) 2012-08-08
AU2006302443B2 (en) 2012-07-26

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